Prostate cancer is the second most common cancer and the second most common cause of cancer mortality in men in the United States. A critical challenge in the clinical management of prostate cancer is the development of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT). ADT is a mainstay in the treatment regimen following a diagnosis of advanced prostate cancer. However, after an initial response to ADT, the disease invariably progresses to CRPC, which is incurable. The median survival time for patients with CRPC is less than 2 years. Therefore, there is an urgent need to develop effective strategies to prevent and treat CRPC.

Recent advances have demonstrated that two intracellular signaling pathways promote the development of CRPC. One is the androgen receptor (AR) pathway, which remains activated in the cancer cells despite a low-androgen environment. The other is the oncogenic PI3K/AKT pathway, which is constantly active due to the loss of an important tumor suppressor gene. Interestingly, these two pathways crosstalk through reciprocal inhibition, suggesting that one of these pathways is utilized by the cancer cells to promote tumor growth, while the other is subdued. This has significant therapeutic implication as interventions targeting only the predominant survival pathway could lead to the activation of the alternative survival pathway and render the treatments ineffective. Therefore, it is imperative that both pathways be targeted simultaneously in the treatment of advanced prostate cancer.

Studies conducted in our laboratory have shown that berberine, a natural compound that has a long history of use in herbal medicine, inhibits both the AR and the PI3K/AKT pathways in prostate cancer cells. This unique property provides a strong rationale of using berberine in the treatment of CRPC. The objective of this project is to understand how berberine exerts its effects against prostate cancer cells and to test the potential of berberine in treating CRPC. If successful, this study would equip clinicians with an agent to prevent prostate cancer relapse after androgen deprivation and to treat patients who have developed CRPC. We project that we will have sufficient data to initiate a clinical trial by the time the proposed study is completed. A patient-related outcome could be expected within a decade.